Human endogenous retroviruses (HERVs) are remnants of retroviruses that integrated into the human genome 6-15 million years ago and have remained an integral part of the genome throughout evolution. One significant type of HERV is ERV-9; approximately 5% of the total human genome comprises sequences from this retrovirus family of 30-40 members (Costas and Naveira, Mol. Biol. Evol. 17(2):320-330, 2000). The human genome contains approximately 50 copies of ERV-9 along with 3000-4000 copies of solitary elements of ERV-9 regulatory regions, called long terminal repeats (LTRs) (Pi et al., Proc. Natl. Acad. Sci. 101(3):805-810, 2004).
Solitary LTRs include U3, R and U5 regions, but do not contain any viral genes. U3 contains promoter and enhancer elements that drive expression of genes located proximally to the LTR. In addition, the U3 enhancer contains 14 tandemly repeated subunits with recurrent motifs. The 5′ end of the R region marks the initiation site of retroviral RNA synthesis. The U5 region is also transcribed (Pi et al., Proc. Natl. Acad. Sci. 101(3):805-810, 2004).
During primate evolution, HERV LTRs were self-replicated and inserted into various chromosomal sites. HERV LTR sequences were once thought to be merely selfish DNA with no relevant cellular function. However, some studies suggest that the enhancer and promoter elements in the U3 region of HERV LTRs initiate and promote transcription of host genes located immediately downstream of the LTRs. ERV-9 LTR sequences have been identified in proximity to several human genes, including the β-globin locus control region (β-LCR) (Ling et al., J. Virol. 76(5):2410-2423, 2002), the embryonic axin gene (Ling et al., J. Virol. 76(5):2410-2423, 2002) and ZNF80 (Di Cristofano et al., Nucleic Acids Res. 23(15):2823-2830, 1995). The ability of HERV LTR sequences to enhance expression of proximal genes can result in upregulation of genes that contribute to diseases such as cancer. Thus, a need exists to inhibit HERV enhancer activity.